Prodrugs of antihypercholesterolemic compounds

ABSTRACT

Prodrugs of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors which are useful as antihypercholesterolemic agents and are represented by the following general structural formula (I): ##STR1## are disclosed.

This is a division of application Ser. No. 902,894, filed Sept.2, 1986,now U.S. Pat. No. 4,837,205.

BACKGROUND OF THE INVENTION

Hypercholesterolemia is known to be one of the prime risk factors forischemic cardiovascular disease, such as arteriosclerosis. To date,there is still no effective antihypercholesterolemic agent commerciallyavailable that has found wide patient acceptance. The bile acidsequestrants seem to be moderately effective but they must be consumedin large quantities, i.e. several grams at a time and they are not verypalatable.

There are agents known, however, that are very activeantihypercholesterolemic agents that function by limiting cholesterolbiosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agentsinclude the natural fermentation products compactin and mevinolin and avariety of semisynthetic and totally synthetic analogs thereof.

The naturally occurring compounds and their semi-synthetic analogs havethe following general structural formulae: ##STR2## wherein X ishydrogen, C₁₋₅ alkyl or C₁₋₅ alkyl substituted with a member of thegroup consisting of phenyl, dimethylamino or acetylamino;

R' is ##STR3## wherein Q is ##STR4## R₂ is hydrogen or hydroxy; R₁ ishydrogen or methyl; and

a, b, c and d are single bonds, one of a, b, c and d is a double bond ora and c or b and d are double bonds provided that when a is a doublebond, Q is ##STR5##

The totally synthetic antihypercholesterolemic compounds are disclosedin U.S. Pat. No. 4,375,475 and have the following general structuralformulae: ##STR6## wherein R" is: ##STR7## wherein: E is --CH₂ --, --CH₂CH₂ -- or --CH═CH--;

R₃ and R₄ are independently C₁₋₃ alkyl, fluoro, bromo or chloro; and

R₅ is phenyl, benzyloxy, substituted phenyl or substituted benzyloxy inwhich the phenyl group in each case is substituted with one or moresubstituents selected from C₁₋₃ alkyl, fluoro, bromo or chloro.

SUMMARY OF THE INVENTION

This invention relates to novel compounds which are prodrugs of knownHMG-CoA reductase inhibitors and which are bioconverted followingsystemic administration to useful antihypercholesterolemic agents.Specifically, the compounds of this invention include acetal and ketalderivatives of the dihydroxy acid form of compactin, mevinolin, CS514,the dihydro and tetrahydro analogs thereof and the totally syntheticHMG-CoA reductase inhibitors. Additionally, pharmaceutical compositionsof these prodrugs, as the sole therapeutic agent, and in combinationwith bile acid sequestrants are disclosed.

DETAILED DESCRIPTION OF THE INVENTION

The specific prodrugs of this invention are the compounds represented bythe following general structural formula (I): ##STR8## wherein: R isselected from a group consisting of:

(a) ##STR9## wherein: n is 1 to 5;

R¹ is hydrogen or methyl;

A is ##STR10## in which R² is hydrogen or hydroxyl; B is ##STR11## inwhich R³ is hydrogen or hydroxyl; a, b, c and d represent single bonds,one of a, b, c and d represents a double bond or both a and c or both band d represent double bonds, provided that when a is a double bond, Ais ##STR12## and when d is a double bond, B is ##STR13## or

(b) ##STR14## wherein: E is --CH₂ --, --CH₂ CH₂ -- or --CH═CH--;

R⁴ and R⁵ are independently C₁₋₃ alkyl, fluoro, bromo or chloro; and

R⁶ is phenyl, benzyloxy, substituted phenyl or substituted benzyloxy inwhich the phenyl group in each case is substituted with one or moresubstituents selected from C₁₋₃ alkyl, fluoro, bromo or chloro;

R⁷ is hydrogen or C₁₋₆ alkyl;

R⁸ is C₁₋₆ alkyl; and

R⁹ is C₁₋₆ alkyl, C₁₋₆ acyloxy-C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyloxy C₁₋₆alkyl or a group selected from

(1) (5-(1,1-dimethylethyl)-2-oxo-1,3-dioxol-4-yl)methyl; or

(2) 2-(β-D-galactosidyl)ethyl.

One embodiment of this invention are the compounds of the formula (I)wherein R is the group (b). Illustrative of this embodiment arecompounds wherein E is --CH═CH--; R⁴ and R⁵ are independently C₁₋₃ alkyland R⁶ is substituted phenyl. More specifically, group (b) is: ##STR15##

Exemplifying this embodiment are the class of compounds wherein R⁹ isC₁₋₆ alkyl and specifically, ethyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)]1,1'-biphenyl]-2-yl)ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate.

A second class of compounds exemplifying this embodiment contain thosecompounds wherein R⁹ is C₁₋₆ acyloxy-C₁₋₆ alkyl and specifically(2,2-dimethyl-1-oxopropoxy)methyl6-(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate.

A third class of compounds exemplifying this embodiment contain thosecompounds wherein R⁹ is C₁₋₆ alkoxyacyloxy-C₁₋₆ alkyl, such as[[(1,1-dimethylethoxy)carbonyl]oxy]methyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate.

A fourth class of compounds exemplifying this embodiment contain thosecompounds wherein R⁹ is[5-(1,1-dimethylethyl)-2-oxo-1,3-dioxol-4-yl]methyl, such as[5-[(1,1-dimethylethyl)-2-oxo-1,3-dioxol-4-yl]]-methyl 6(S)-E-[2-[(4-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate.

Another class of compounds exemplifying this embodiment contain thosecompounds wherein R⁹ is 2-(β-D-galactosidyl)ethyl, such as2-(β-D-galactosidyl)ethyl6-(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate.

A second embodiment of this invention are the compounds of the formula(I) wherein R is the group (a).

The compounds of this invention are conveniently prepared by either (1)an acetalization or ketalization of the ring opened dihydroxy ester formof known HMG-CoA reductase inhibitors; or (2) the acetalization orketalization of the ring opened dihydroxy acid form of known HMG-CoAreductase inhibitors followed by esterification according to thefollowing synthetic pathway; ##STR16##

The compounds of the formula (1) are known in the art. When R is thegroup (a), the compounds of the formula (1) are the ring openeddihydroxy acid form of compactin, mevinolin, CS514 and their dihydro andtetrahydro analogs which are readily available or may be preparedaccording to the fermentation procedures disclosed in U.S. Pat. Nos.3,983,140; 4,049,495; 4,231,938; 4,294,846 and 4,517,373 and thehydrogenation procedures disclosed in U.S. Pat. No. 4,351,844. When R isthe group (b), the compounds of the formula (1) are readily available byutilizing the procedures described in U.S. Pat. No. 4,375,475.

According to the first reaction sequence, the compounds of the formula(1) are neutralized with a primary amine, such as α-methylbenzylamine,to form the ammonium salt which is then treated with the appropriateorganohalide, R⁹ hal, wherein hal is bromo or chloro, to afford thecompounds of the formula (2). The compounds of the formula (2) are thentreated with the appropriate aldehyde, ketone or enol ether thereof inthe presence of a catalytic amount of an acid, such as p-toluenesulfonicacid, to give the compounds of the formula (I). The sequence of thereactions may be reversed so that the acetal or ketal of the formula (3)is prepared and then esterified to obtain the compounds of the formula(I).

The compounds of this invention are useful as prodrugs ofantihypercholesterolemic agents for the treatment of arteriosclerosis,hyperlipidemia, familial hypercholesterolemia and the like diseases inhumans. They may be administered orally in the form of a capsule, atablet, or the like. Doses may be varied, depending on the age,severity, body weight and other conditions of human patients but dailydosage for adults is within a range of from about 20 mg to 2000 mg(preferably 20 to 100 mg) which may be given in two to four divideddoses. Higher doses may be favorably employed as required.

The compounds of this invention may also be coadministered withpharmaceutically acceptable nontoxic cationic polymers capable ofbinding bile acids in a non-reabsorbable form in the gastrointestinaltract. Examples of such polymers include cholestyramine, colestipol andpoly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide]. Therelative amounts of the compounds of this invention and these polymersis between 1:100 and 1:15,000.

The ability of the compounds of this invention to act as prodrugs ofantihypercholesterolemic agents is demonstrated in a standard in vivopharmacological assay in dogs.

Eight male beagle dogs weighing from 7.2-12.9 kilograms approximately4-5 years old were fed a low cholesterol, semi-synthetic diet once a dayin the morning in sufficient quantity to maintain a constant bodyweight. The animals were trained to consume their entire ration eachday. Cholestyramine, 12 g, was administered daily in the diet. Thisamount routinely resulted in an average reduction in plasma totalcholesterol of approximately 35%. Dogs were bled twice a week from thejugular vein and plasma cholesterol was determined after extraction andsaponification by a colorimetric procedure (Liebermann Burchard). Afterthe establishment of pretreatment plasma cholesterol levels, one or moredogs were treated with daily doses of test compound mixed directly intothe diet for 14 days.

Representative of the pharmacological activity of the compounds of thisinvention tabulated below are a number of compounds and the percentagedecrease in cholesterol levels in dogs at specified dosages after 14days of treatment.

    ______________________________________                                         ##STR17##                                                                                                  Percent                                                                       Reduction in                                    Compounds          Dosage     Plasma                                          R.sup.7                                                                            R.sup.8                                                                              R.sup.9        (mg/kg/day)                                                                            Cholesterol                               ______________________________________                                        Me   Me     CH.sub.2 CH.sub.3                                                                            8        32                                        Me   Me                                                                                    ##STR18##     8        27                                        ______________________________________                                    

Included within the scope of this invention is the method of treatingarteriosclerosis, familial hypercholesterolemia or hyperlipidemia whichcomprises administering to a subject in need of such of the compounds offormula (I) or pharmaceutical compositions thereof.

The following examples illustrate the preparation of the compounds ofthe formula (I) and their incorporation into pharmaceutical compositionsand as such are not to be considered as limiting the invention set forthin the claims appended hereto.

EXAMPLE 1 Preparation of Ethyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate

To 2.0 g (5 mmol) ethyl7-[(4'-fluoro-3,3',5trimethyl)[1,1'-biphenyl]-2-yl]-3(R),5(S)-dihydroxy-6(E)-heptenoateand 0.72 g (10 mmol) 2-methoxypropene dissolved in 25 ml DMF was added10 mg of p-toluenesulfonic acid monohydrate at room temperature. Afterstirring for 16 hours, the reaction mixture was taken up in 125 mldiethyl ether and washed with 3×25 ml portions of water, 25 ml saturatedsodium bicarbonate solution, 25 ml H₂ O, brine and dried. The solventwas removed in vacuo to give an oil that was purified by flashchromatography on silica gel eluting with hexane:Et₂ O (4:1). Solventremoval left an oil which was triturated to give the above titledcompound as a white solid, m.p. 76°-78°.

Anal. Calc'd for C₂₇ H₃₃ FO₄ : C, 73.61; H, 7.55 Found: C, 73.67; H,7.87

EXAMPLE 2 Preparation of (2,2-Dimethyl-1-oxopropoxy)methyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate(a) PivaloyloxymethylE-7-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)-3(R),5(S)-dihydroxyhept-6-enoate(2a)

To 29.62 g (60 mmol) of the α-methylbenzylammonium salt of7-[(4'-fluoro-3,3',5-trimethyl)[1,1-biphenyl]-2-yl]-3(R),5(S)-dihydroxy-6(E)-heptenoicacid in 165 ml DMF was added 18.07 g (120 mmol) chloromethyl pivalate,0.8 g potassium carbonate and 4.8 ml of 10% aqueous potassium iodide andthe resulting mixture stirred at room temperature for 18 hours. Thereaction mixture was diluted with 400 ml diethyl ether and this waswashed with 3×200 ml portions H₂ O, 75 ml saturated NaHCO₃ solution,brine and dried. Solvent removal in vacuo gave an oil that was purifiedby flash chromatography on silica gel eluting with 5% isopropanol/hexaneto give an oil. This was triturated with hexane to give pure desiredproduct as a white solid, m.p. 97°-98°.

(b) (2,2-Dimethyl-1-oxopropoxy)methyl6(S)-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate

To 1.46 g (3.0 mmol) compound 2a in 15 ml DMF was added 0.43 g (6.0mmol) 2-methoxypropene and 10 mg p-toluenesulfonic acid monohydrate withstirring. After 18 hours at room temperature the reaction mixture wastaken up in 75 ml Et₂ O and washed successively with 3×15 ml H₂ O, 15 mlsaturated NaHCO₃ solution, 15 ml H₂ O, brine and dried. Solvent removalin vacuo gave an oil which was purified by flash chromatography onsilica gel eluting with 25% isopropanol/hexane to give a solid. This wasrecrystallized from hexane to afford the above titled compound, m.p.120°-121°.

Anal. Calc'd for C₃₁ H₃₉ FO₆ : C, 70.70; H, 7.46 Found: C, 70.62; H,7.53

EXAMPLE 3 Preparation of [[(1,1-Dimethylethoxy)carbonyl]oxy]methyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)acetate(a) ([(Dimethylethoxy)carbonyl]oxy)methylE-7-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]-3(R),5(S)-dihydroxyhept-6-enoate (3a)

To 0.79 g (2 mmol) of the α-methylbenzylammonium salt of7-[(4'-fluoro-3,3',5-trimethyl)[1,1-biphenyl]-2-yl]-3(R),5(S)-dihydroxy-6(E)-heptenoicacid in 6 ml DMF at room temperature was added 0.67 g (4 mmol),chloromethyl t-butylcarbonate, 60 mg sodium iodide and 20 mg potassiumcarbonate with stirring. After 24 hours at room temperature the reactionmixture was poured into 25 ml H₂ O and this was extracted with 5×30 mlportions of diethyl ether. The combined organic extracts were washedwith 2×25 ml portions of H₂ O, brine and dried. Solvent removal in vacuogave a yellow oil that was purified by flash chromatography on silicagel eluting with 5% isopropanol/hexane to give a white residue. This wastriturated with 5% isopropanol/hexane to give the desired product as awhite solid, m.p. 103°-104°.

(b) [[(1,1-Dimethylethoxy)carbonyl]oxy]methyl 6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate

To 1.02 g (2 mmol) compound 3a in 5 ml DMF at room temperature was added0.288 g (4 mmol) 2-methoxypropene and 20 mg p-toluenesulfonic acidmonohydrate and the resulting solution was stirred overnight. This waspoured into 75 ml cold H₂ O and extracted with 4×75 ml portions ofdiethyl ether. The combined organic extracts were washed with 3×50 ml H₂O, 2×25 ml portions of saturated NaHCO₃ solution, brine, and dried. Thesolvent was removed in vacuo to give a yellow oil that was purified byflash chromatography on silica gel eluting with hexane:diethyl ether(5:1) to give an oil. This was triturated with hexane to provide theabove titled compound as a white solid, m.p. 98°-100°.

Anal. Calc'd for C₃₁ H₃₉ FO₇ : C, 68.61; H, 7.24 Found: C, 68.72; H,7.45

EXAMPLE 4 Preparation of[5-(1,1-Dimethylethyl)-2-oxo-1,3-dioxol-4-yl]methyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate(a) (5-[(1,1-Dimethylethyl)-2-oxo-1,3-dioxol-4-yl])methylE-7-(4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl)-3(R),5(S)-dihydroxyhept-6-enoate(4a)

To 4.94 g (10 mmol) α-methylbenzylammonium salt of7-[(4'-fluoro-3,3',5-trimethyl)[1,1-biphenyl]-2-yl]-3(R),5(S)-dihydroxy-6(E)-heptenoicacid in 35 ml DMF at room temperature was added 2.59 g (11 mmol)4-bromomethyl-5-tert-butyl-2-oxo-1,3-dioxolene dropwise followed by 100mg of potassium carbonate. This suspension was stirred at roomtemperature for 16 hours. The solvent was removed in vacuo (<50° C.) andthe residue was taken up in 350 ml diethyl ether. This was washed with4×75 ml portions of H₂ O, brine and dried. The solvent was removed invacuo to give an oil which was purified by flash chromatography onsilica gel eluting with 8% isopropyl/hexane to give the desired productas a clear oil.

(b) (5-[(1,1-Dimethylethyl)-2-oxo-1,3-dioxol-4-yl])-methyl6(S)-E-[2-(4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl)ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate

To 1.6 g (3 mmol) compound 4a in 5 ml DMF at room temperature was added0.433 g (6 mmol) 2-methoxypropene and 20 mg p-toIuenesuItonic acidmonohydrate with stirring. After 24 hours the reaction mixture waspoured into 75 ml cold H₂ O and extracted with 4×75 ml portions ofdiethyl ether. The combined organic extracts were washed with 3×50 mlportions of H₂ O, 2×25 ml portions of saturated NaHCO₃ solution, 50 mlH₂ O, brine and dried. Solvent removal in vacuo gave a yellow oil thatwas purified by flash chromatography on silica gel eluting withhexane:diethyl ether (3:1) to give a clear oil. This was triturated withhexane to give the above titled compound as a white solid, m.p. 88°-90°.

Anal. Calc'd for C₃₃ H₃₉ FO₇ : C, 69.94; H, 6.94 Found: C, 70.06; H,7.15.

EXAMPLE 5 Preparation of 2-(β-D-Galactosidyl)ethyl6(S)-E-[2-[(4'-fluoro-3,3',5-trimethyl)[1,1'-biphenyl]-2-yl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate(a)6(S)-E-[2-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-aceticacid (5a)

To 0.2 g (0.5 mmol) α-methylbenzylammonium salt of 7-[(4-fluoro-3,3',5-trimethyl)[1,1-biphenyl]-2-yl]-3(R),5(S)-dihydroxy-6(E)-heptenoicacid in 5 ml DMF was added 0.072 g (1.0 mmol) 2-methoxypropene and 2 mgp-toluenesulfonic acid monohydrate at room temperature and the resultingsolution stirred overnight at room temperature. After 18 hours thereaction mixture was diluted with 15 ml diethyl ether and washedsuccessively with 3×3 ml portions of H₂ O, 1 ml saturated NaHCO₃solution, 3 ml H₂ O, brine and dried. Solvent removal gave a gum thatwas recrystallized from hexane to give the desired product as a solid.

(b) 2-(β-D-Galactosidyl)ethyl6(S)-E-[2-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)ethenyl]-2,2-dimethyl-1,3-dioxane-4(R)-acetate

To 1.03 g (2.5 mmol) 2-bromoethyl-β-D-galactopyranoside [prepared by themethod of G. Magmusson et al., Carbohydr. Res., 125, 237 (1984)]dissolved in 10 ml DMF was added 2.5 ml of a 1N NaOH solution (slightexotherm) and this was stirred for 1 hour. Then, 0.035 g (0.25 mmol) K₂CO₃ was added followed by 0.2 ml of a 10% NaI solution and a solution of0.86 g (3.0 mmol) compound 5a in 5 ml DMF. The resulting mixture wasstirred at room temperature for 3 days.

The solvent was removed in vacuo and the residue purified by flashchromatography on silica gel eluting with 10% MeOH/CHCl₃ to give theabove titled compound as a white solid, m.p. 71°-73°.

Anal. Calc'd for C₃₃ H₄₃ FO₁₀.2H₂ O: C, 60.54; H, 7.24 Found: C, 60.61;H, 7.02.

EXAMPLES 6-14

The following compounds in Tables I and II are prepared according to thegeneral procedures of Examples 1 and 2 utilizing the appropriatestarting materials.

                  TABLE I                                                         ______________________________________                                         ##STR19##                                                                    Compound                                                                      No.     E           R.sup.7 R.sup.8                                                                            R.sup.9                                      ______________________________________                                        6       CH.sub.2 CH.sub.2                                                                         Et      H    Me                                           7       CHCH         -nPr   Me                                                                                  ##STR20##                                   8       CH.sub.2                                                                                   ##STR21##                                                                            Et                                                                                  ##STR22##                                   9       CHCH         -n-amyl                                                                              H     -nBu                                        ______________________________________                                    

                                      TABLE II                                    __________________________________________________________________________     ##STR23##                                                                    Com-                                                                          pound                                                                         No. T        T.sup.1                                                                          T.sup.2                                                                          R.sup.7                                                                          R.sup.8                                                                          R.sup.9                                              __________________________________________________________________________    10                                                                                 ##STR24##                                                                             H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.2 CH.sub.3                                    11                                                                                 ##STR25##                                                                             H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                          ##STR26##                                           12                                                                                 ##STR27##                                                                             OH CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                          ##STR28##                                           13                                                                                 ##STR29##                                                                             H  H  CH.sub.3                                                                         CH.sub.3                                                                          ##STR30##                                           14                                                                                 ##STR31##                                                                             H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                          ##STR32##                                           __________________________________________________________________________

EXAMPLE 15

As a specific embodiment of a composition of this invention, 20 mg ofthe compound of Example 1 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size 0 hardgelatin capsule.

What is claimed is:
 1. A compound represented by the general structuralformula (I): ##STR33## wherein: R is (a) ##STR34## wherein: n is 1 to5;R¹ is hydrogen or methyl; A is ##STR35## in which R² is hydrogen orhydroxyl; B is ##STR36## in which R₃ is hydrogen or hydroxyl; a, b, cand d represent single bonds, one and only one of a, b, c and drepresents a double bond or both a and c only or both b and d onlyrepresent double bonds, provided that when a is a double bond, A is##STR37## and when d is a double bond, B is ##STR38## R⁷ is hydrogen orC₁₋₆ alkyl; R⁸ is C₁₋₆ alkyl; and R⁹ is C₁₋₆ alkyl, C₁₋₆alkanoyloxy-C₁₋₆ alkyl or C₁₋₆ alkoxy carbonyloxy-C₁₋₆ alkyl or a groupselected from(1) (5-(1,1-dimethylethyl)-2-oxo-1,3-dioxol-4-yl)methyl; or(2) 2(β-D-galactosidyl)ethyl.
 2. A compound of claim 1 wherein R⁹ isC₁₋₆ alkyl.
 3. A compound of claim 1 wherein R⁹ is C₁₋₆ alkanoloxy-C₁₋₆alkyl.
 4. A compound of claim 1 wherein R⁹ is C₁₋₆alkoxycarbonyloxy-C₁₋₆ alkyl.
 5. A hypocholesterolemic, hypolipidemicpharmaceutical composition comprising a nontoxic therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 6. A method of inhibiting cholesterol biosynthesiscomprising the administration to a subject in need of such treatment anontoxic therapeutically effective amount of a compound of claim 1.